tbuckley/cabot-search huggingface dataset:
Regulation of proton partitioning in kinase-activating acute myeloid leukemia and its therapeutic implication
Authors: Cheuk-Him Man, Xiaoyuan Zeng, Wing Lam, Timothy C. C. Ng, Tsz-Ho Kwok, Kenny C. C. Dang, Thomas W. Y. Leung, Nelson K. L. Ng, Stephen S. Y. Lam, Chae-Yin Cher, Anskar Y. H. Leung
Journal: Leukemia (2022)

Abstract Gain-of-function kinase mutations are common in AML and usually portend an inferior prognosis. We reported a novel mechanism whereby kinase mutants induced intracellular alkalization characteristic in oncogenesis. Thirteen kinases were found to activate sodium/hydrogen exchanger (NHE1) in normal hematopoietic progenitors, of which FLT3-ITD, KRAS G12D , and BTK phosphorylated NHE1 maintained alkaline intracellular pH (pHi) and supported survival of AML cells. Primary AML samples with kinase mutations also showed increased NHE1 phosphorylation and evidence of NHE1 addiction. Amiloride enhanced anti-leukemic effects and intracellular distribution of kinase inhibitors and chemotherapy. Co-inhibition of NHE1 and kinase synergistically acidified pHi in leukemia and inhibited its growth in vivo. Plasma from patients taking amiloride for diuresis reduced pHi of leukemia and enhanced cytotoxic effects of kinase inhibitors and chemotherapy in vitro. NHE1-mediated intracellular alkalization played a key pathogenetic role in transmitting the proliferative signal from mutated-kinase and could be exploited for therapeutic intervention in AML.
Mesaconate is synthesized from itaconate and exerts immunomodulatory effects in macrophages
Authors: Wei He, Antonia Henne, Mario Lauterbach, Eike Geißmar, Fabian Nikolka, Celia Kho, Alexander Heinz, Catherine Dostert, Melanie Grusdat, Thekla Cordes, Janika Härm, Oliver Goldmann, Anouk Ewen, Charlène Verschueren, Julia Blay-Cadanet, Robert Geffers, Hendrikus Garritsen, Manfred Kneiling, Christian K. Holm, Christian M. Metallo, Eva Medina, Zeinab Abdullah, Eicke Latz, Dirk Brenner, Karsten Hiller
Journal: Nature Metabolism (2022)
EPID-01. Differences in first-line treatment but comparable survival outcomes for pediatric brainstem and non-brainstem high-grade gliomas in the Netherlands – a population-based study
Authors: Raoull Hoogendijk, Jasper van der Lugt, Josh Baugh, Leontien Kremer, Eelco Hoving, Dannis van Vuurden, Henrike Karim-Kos
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: Pediatric high-grade gliomas (pHGG) are among the most devastating childhood cancers. Due to their limited treatment options and tumor biology, brainstem (BS) pHGG are considered to have worse survival outcomes compared to non-brainstem (NBS) pHGG. METHODS: Detailed clinical data were gathered by trained registrars for all children diagnosed with a pHGG (including radiologically diagnosed brainstem tumors) in the Netherlands for the period 2003-2017. Tumors were grouped into BS and NBS tumors according to the ICD-O-3 topography codes. Differences in treatment characteristics were tested with the Chi-squared, Fisher exact or Mann-Whitney-Wilcoxon test. Median survival time was determined by Kaplan-Meier method. Trends and survival differences were tested with Cox Proportional-Hazards Models. RESULTS: In total, 276 pHGG patients (BS n=166, NBS n=110) were diagnosed during 2003-2017. Differences in first line treatment were found for neurosurgery (25% of BS versus 95% of NBS patients, p&amp;lt;0.001) and systemic therapy (20% of BS versus 70% of NBS, p&amp;lt;0.001). Notable, 10% of BS patients received temozolomide compared to 55% of NBS patients (p&amp;lt;0.001). No significant difference was found for first-line radiotherapy. However, total cumulative dose and number of fractions differed significantly (BS: median 44.8 Gy and 16 fractions; NBS: median 57.4 Gy and 30 fractions, both p&amp;lt;0.001), reflecting hypofractionation regimens in BS pHGG. Survival remained stable over time for both BS (p=0.9) and NBS (p=0.3). Median survival time was comparable between BS (9.7 months) and NBS patients (9.8 months, p=0.6).CONCLUSION: Despite differences in treatment characteristics we found comparable survival outcomes for BS and NBS pHGG. It remains unclear why survival for both BS and NBS pHGG in this retrospective population-based study is substantially inferior to published data. If the underlying reasons can be found in differences in treatment characteristics, data type (hospital-based versus population-based) or incompleteness of non-microscopically verified cases, is subject to further research.
Real world data of neoadjuvant and adjuvant chemotherapy in head neck osteosarcoma: Experience from a tertiary care center in India.
Authors: Arnav Tongaonkar, Vijay Maruti Patil, Vanita Noronha, Nandini Sharrel Menon, Shweta Jogdhankar, Kumar Prabhash
Journal: Journal of Clinical Oncology (2022)

e18012 Background: The head and neck (HN) region is a rare sub-site of osteosarcoma(OGS), with less than 10% of all cases of osteosarcoma and &lt; 1% of all the head and neck malignancies . The evidence pertaining to the treatment of OGS of the head &amp; neck region is limited. The role of adjuvant chemotherapy is evolving and research in this field is limited by the rarity of this tumour. However, in multiple small series, adjuvant or neoadjuvant chemotherapy has been found to be beneficial in head and neck OGS. To this end, we have audited our practice of the last 10 years to see the pattern of care, outcomes and advancements in the chemotherapy of HN OGS. Methods: We maintain a record at our outpatient department of patients receiving neoadjuvant and adjuvant chemotherapy. We conducted a database search spanning the data from 2010 to 2020, using the keywords: osteosarcoma, osteogenic sarcoma, OGS and head neck region, maxilla, skull base. Any adult patients who received chemotherapy in the adjuvant or neoadjuvant setting were selected for this study. The baseline demographics, patterns of chemotherapy administration and outcomes were documented. We analysed the data using SPSS descriptive statistical analysis. Survival analysis for progression-free survival and overall survival was done using the Kaplan-Meyer method. Results: 30 patients of HN OGS were treated with neoadjuvant chemotherapy (NACT) or adjuvant chemotherapy (ACT) at our centre from 2010 to 2020. The median age was 25 years, with a male preponderance (n = 21, 70%). The sites of disease were maxilla- 15(50%), mandible- 11 (37%), alveolus- 2 (6.6 %), orbit- 1 (3.3%), masticator space - 1 (3.3%). Out of the study population, 18 patients (60%) received NACT, 17 patients (56%) received ACT, 5(16%) patients received both NACT and ACT. 23 patients (76.6 %) underwent surgical resection, with R0 resection achieved in 17 (56.6%) and R1 in 3 patients(10%). 16 patients (53.3%) received adjuvant radiotherapy. Median progression-free survival was 16.10 months (95% CI: 10.30-21.89). Median overall survival (OS) was 22.56 months (95%CI: 11.16-33.96). 2 years OS was 49.1% (standard error 9.6). Conclusions: The patterns of use of neoadjuatnt and adjuvant chemotherapy in HN OGS are variable. Overall, the outcomes of HN OGS remain unsatisfactory. Further efforts are warranted in this direction to standardise an algorithm for chemotherapy. Further intensification of therapy may be required to improve patient outcomes.
Can immediate reconstruction with submandibular gland transposition broaden indications for transoral surgery for tonsillar cancer?
Authors: Wang Robert, Jo-Lawrence Bigcas, Oluwafunmilola Okuyemi, Albert Yang, Allen Young
Journal: Journal of Clinical Oncology (2022)

e18054 Background: Stratification based on pathologic parameters allows for reduced adjuvant radiotherapy in intermediate risk and observation alone for low risk oropharyngeal p16+ cancer (E3311 ECOG-ACRIN trial). Selection for transoral surgery (TOS), usually robotically assisted, for tonsillar cancers depends on the size and invasiveness of the primary tumor, involvement of adjacent parts such as the soft palate, proximity to external carotid artery branches, medial ipsilateral carotid artery that might be exposed with radical resection, and the likelihood of substantial communication between the oropharynx and internal neck structures. Postoperative recovery can be associated with substantial pain and dysphagia and a length of stay of &gt; 5 days. There is a paucity of simple options for sealing the neck from the pharynx to prevent neck infection, exposure of larger vessels and salivary fistula, so large and deep tonsillar cancers are usually given chemoradiation. Larger surgical defects healing secondarily tend to require longer recoveries due to dysphagia and odynophagia. Methods: A prospective study of vascularized ipsilateral submandibular gland transposition flaps to primarily repair the surgical defect after TOS to resect previously untreated tonsillar cancers was performed from 2019 to 2022. A total of 19 patients underwent resection and repair. These included those with cancers extending to the soft palate (4) and medial position of internal carotid artery adjacent to the tumor (1). All had obvious communication between the neck and the pharynx after TOS, and had branches of the facial and external carotid arteries to the deep resection site ligated with neck dissection, prior to TOS. The submandibular gland flaps were sewn in place using robot assistance and hand. One patient had an extended flap with accompanying submental skin to repair the soft palate. Results: Partial dehiscence superiorly at the palate was the most common complication at 11%. None developed salivary fistulas or deep neck infections. Iatrogenic facial artery pedicle injury that was repaired occurred in one case. Oral intake was started at 1-3 days and length of stay averaged 5 days. There were no bleeding episodes at the TOS sites of cancer resection. All resections had clear margins. All submandibular gland flaps survived, with one patient having attached adipose tissue debrided in the office, healing uneventfully thereafter. Conclusions: The ability to primarily repair after resection of more extensive tonsillar cancers, that leave large communications between the pharynx and the neck, with a readily accessible and easy to harvest submandibular gland flap may change those previously selected for chemoradiation to be able to have TOS instead as initial treatment. This would allow for more pathological risk assessment of tonsil cancers and decreased adjuvant treatment when appropriate.
Unexpected low metastatic potential to lymph-nodes of isolated tumor cell and cluster-cord in ISUP 5 prostate adenocarcinoma: A mono-institutional cohort analysis with clinic-pathological correlation
Authors: M. Cieri, V. Belsito, A. Bressan, M. Valeri, C. De Carlo, G. Lughezzani, L.M. Terracciano, P. Colombo
Journal: European Urology (2022)
Assessing compartmentalisation of small non-coding RNAs by fractionation of lipoproteins and extracellular vesicles of human plasma
Authors: I Teng, C Gutmann, K Takov, M Mayr
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: None. Background/Introduction Circulating small non-coding RNAs (ncRNAs), such as microRNAs (miRNAs) and YRNAs, have been implicated in intercellular communication and as biomarkers for cardiometabolic diseases. The putative carriers of ncRNAs are lipoproteins, extracellular vesicles (EVs) and RNA-binding proteins. However, the lack of reliable separation methods for EVs and lipoproteins from human blood hampers the assignment of small ncRNA signatures to different carriers. Purpose To study which classes of ncRNAs are carried by EVs or lipoproteins in the circulation. Methods &amp; Results In order to minimise the co-isolation of lipoproteins and EVs, size-exclusion chromatography (SEC) was established to improve resolution of nanoparticles from plasma. Mass spectrometry and immunoblotting for EV markers (syntenin-1 and CD9) and apolipoproteins (ApoA1 and ApoB for high- and low-density lipoproteins, respectively) were used to characterise the isolated preparations and identify co-isolating species. Quantitative real-time PCR of each carrier-rich fraction after SEC showed that miRNAs were mainly detected in the late-eluting fractions, enriched in ApoA1-containing lipoproteins. Only a small proportion of miRNAs was associated with fractions rich in albumin or in EVs. On the other hand, YRNAs were predominantly found in the albumin-rich and ApoB-containing fractions. To assess whether lipoproteins are key carriers for ncRNAs, HDL and ApoB immuno-depletion methods were employed. Both lipoprotein depletion methods failed to substantially deplete small ncRNAs from plasma. Conclusion We studied the distribution of circulating ncRNAs amongst different SEC fractions from human plasma. We have observed a minor role for lipoproteins as carriers of ncRNAs. Further investigation will focus on using SEC fractionation to assess EVs and RNA-binding proteins and their role as ncRNA carriers in plasma.
Optimizing Treatment of Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Authors: Anthony Mato
Journal: Journal of the National Comprehensive Cancer Network (2022)

Tremendous progress has been made in the treatment of relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) over the past few decades, starting with the development of glucocorticoids and alkylating agents, moving to combination chemotherapy, and then to chemoimmunotherapy. More recently, the advent of targeted agents has led to significant improvements in overall survival, progression-free survival, and quality of life. Most patients with R/R CLL and SLL are now treated with 1 of 5 approved targeted therapies rather than chemoimmunotherapy as standard of care. There are 2 main chemotherapy-free approaches in the R/R setting: Bruton’s tyrosine kinase inhibition and venetoclax-based therapy. Treatment after disease progression on first-line therapy depends on the initial choice of therapy, reason for discontinuation of prior lines of therapy, and available options.
Orally administered 5-aminolevulinic acid can cause intraoperative hypotension in patients with bladder cancer undergoing transurethral resection
Authors: Y. Ishikawa, U. Sho, K. Ishihara, K. Hirose, T. Soma, M. Fujiwara, M. Kobayashi, B. Fan, Y. Nakamura, Y. Uchida, S. Fukuda, H. Tanaka, S. Yoshida, M. Yokoyama, Y. Matsuoka, Y. Fujii
Journal: European Urology (2022)
Nab-PTX and nab-PTX combined with immune checkpoint inhibitors for relapsed small cell lung cancer.
Authors: Rui Wan, Jie Wang, Jianchun Duan, Zhijie Wang
Journal: Journal of Clinical Oncology (2022)

8576 Background: Despite sensitivity to first-line chemotherapy, most small cell lung cancer (SCLC) patients experience disease progression after initial treatment. Nab-PTX showed comparable anti-tumor activity for relapsed SCLC. Whether immune checkpoint inhibitors (ICIs) combined with nab-PTX could improve clinical outcome for relapsed SCLC has not been fully evaluated. The aim of this study is to evaluate efficacy and safety of nab-PTX and nab-PTX combined with ICIs for relapsed SCLC. Methods: We retrospectively reviewed relapsed SCLC patients who were given nab-PTX (130mg/m2, day1,8 /Q3 weeks) or nab-PTX combined with ICIs (PD-1 or PD-L1), from Feb 2017 to Sep 2021. Clinical data were collected from electronic medical records. The clinical outcome, including progression-free survival (PFS) and overall survival (OS) were assessed using the Kaplan-Meier method and standard Log-rank test. Results: A total of 56 patients with relapsed SCLC were included, 29 and 27 patients received nab-PTX (group A) and nab-PTX combined with ICIs (group B), respectively. Baseline characteristics were well balanced between the groups. Patient characteristics (group A: group B) were as follows; median age 57: 59, male 25(86.2%): 24(88.9%), heavy smoking 23(79.3%): 18(66.7%), ECOG-PS 1 19(65.5%) :19(70.4%), extensive disease 28(96.6%) :25(92.6%), liver metastasis 10(34.5%) :12(44.4%), brain metastasis 8(27.6%) :10(37%), refractory relapse 10(34.5%) :11(40.7%). ORR in group A and B were 17.2% vs 40.7%, and DCR in group A and B were 72.4% vs 66.7%, respectively. The median PFS and median OS were similar between group A and B (median PFS, 2.8months vs 3.2months; median OS, 9.3 months vs 11.0months). PFS and OS according baseline characteristics were showed in the table. Toxicity profile of group B was tolerable as well as group A. Conclusions: This retrospective study indicated nab-PTX combined with ICIs failure to improve clinical outcome for relapsed SCLC when compared with nab-PTX monotherapy.[Table: see text]
RARE-06. Expanding the clinical and molecular spectrum of pituitary blastoma
Authors: Anthony Pak-Yin Liu, Kay Ka-Wai Li, Chit Chow, Shing Chan, Alex Wing-Kwan Leung, Matthew Ming-Kong Shing, Ka-Fai To, Danny Tat-Ming Chan, Godfrey Chi-Fung Chan, Ho-Keung Ng
Journal: Neuro-Oncology (2022)

Abstract Pituitary blastomas (PitB) are rare DICER1-associated tumors that occur exclusively in children &amp;lt; 2 years of age. They are locally aggressive tumors that are driven by a combination of germline and somatic alterations involving DICER1. Here, we report two patients with pituitary neoplasms that expand the clinical and molecular spectrum of PitB. Patient 1 presented at 10 months with diabetes insipidus and was initially diagnosed with pituitary ependymoblastoma. She received debulking, chemotherapy and focal radiation with complete response achieved, but unfortunately died at the age of 8 years due to cerebral edema. Patient 2 was a survivor of infant leukemia who was treated with chemotherapy and then further chemotherapy with cranial irradiation at relapse. The patient was then diagnosed at the age of 8 years with pituitary CNS-PNET, which was treated with craniospinal irradiation and chemotherapy, and had remained in remission for 6 years. Review of histology in both cases indicates presence of neuroendocrine lobules, primitive cells, and Rathke pouch-like glandular structures, with high Ki67, ACTH and PRAME positivity compatible with PitB. Next-generation sequencing revealed presence of two DICER1 mutations (germline frameshifting and somatic missense) in Patient 1, and one somatic missense DICER1 mutation plus loss of heterozygosity in Patient 2 (no germline alteration). Surprisingly, C19MC amplification was also detected in Patient 1. Methylation profiling confirms clustering among our samples and PitB references, but not ETMR references. MicroRNA array revealed decrease in mature microRNA expression and preferential down-regulation of 5p/3p species in tumor compared to control pituitary tissue. In all, PitBs may present with clinical and molecular characteristics not conforming with the classical descriptions. It might be prudent to consider sequencing for DICER1 alteration in pediatric pituitary tumors to facilitate diagnosis of this increasingly heterogeneous rare entity.
Impact of high-deductible health plans on delays in metastatic cancer diagnosis.
Authors: Nicolas Karim Trad, Michael J. Hassett, Fang Zhang, J. Frank Wharam
Journal: Journal of Clinical Oncology (2022)

6503 Background: High-deductible health plans (HDHPs) have grown rapidly in recent years, and now cover over one-half of U.S. workers. Patients in HDHPs are liable for the costs of all cancer-related care until their annual deductible is met, with the exception of screening tests such as colonoscopy and mammography. Due to increased out-of-pocket obligations, patients may postpone presenting for concerning symptoms or diagnostic testing, leading to delayed diagnosis. We therefore assessed the impacts of HDHPs on the timing of metastatic cancer detection. Methods: Using a nationally representative cohort of privately insured members in a national commercial and Medicare Advantage database (2003-2017), we studied 345,401 individuals age 18-64 years whose employers mandated a switch from a low-deductible (≤$500) plan to a high-deductible (≥$1,000) plan. Our control group consisted of 1,654,775 contemporaneous individuals whose employers offered only low-deductible plans. Both groups had a 1-year baseline period when all members were enrolled in low-deductible plans, and we followed members for a maximum of 13.5 years. Participants were matched with respect to age, gender, race/ethnicity, morbidity (ACG) score, poverty level, geographic region, employer size, baseline primary cancer, baseline medical and pharmacy costs, and follow-up duration. We used a validated claims-based algorithm to detect incident metastatic cancer diagnoses. We assessed time to metastatic cancer diagnosis in the baseline period (pre-HDHP switch) and follow-up period (post-HDHP switch) using a weighted Cox proportional hazards model. Results: After matching, there were no systematic differences between the HDHP and control groups with regard to observable baseline characteristics (standardized differences &lt; 0.1). The mean age of participants was 42 years and the mean ACG score was 0.75. 49% were female, 48% lived in low-income neighborhoods, and 62% were White. We detected 1,668 metastatic events over a mean follow-up period of 38 months. There were no differences in time to metastatic diagnosis in the baseline year, prior to the HDHP switch (HR 0.96, p = 0.67). After employer-mandated HDHP switch, HDHP participants had lower odds of metastatic cancer diagnosis (HR 0.88, p = 0.01), indicative of delayed detection relative to the control group. Conclusions: Compared with conventional health plans, HDHPs are associated with delayed detection of metastatic cancer. These findings imply that patients postpone seeking care for concerning symptoms or defer diagnostic testing when exposed to high cost-sharing. Given recent advances that have improved survival of patients with advanced-stage cancers, future research efforts should investigate the impacts of HDHPs on quality of life, engagement in palliative care, and use of treatments in this patient population.
Reduced Implementation and Completion of Average-Risk Annual Fecal Immunochemical Test Colorectal Cancer Screening in Black Patients Aged 45–49 Years
Authors: Gloria D. Coronado, John F. Dickerson, Andrea N. Burnett-Hartman, John M. Carethers, Jeff K. Lee, Mary Ann McBurnie
Journal: Clinical Gastroenterology and Hepatology (2022)